Vitamin D Metabolism, Rickets, and Osteomalacia

ABSTRACT

Rickets in the growing child or adolescent and osteomalacia in the adult develop in a variety of clinical situations and have in common an absence or delay in the mineralization of growth cartilage and in newly formed bone collagen. Classically, deficiency of vitamin D, which is essential for the absorption of dietary calcium, has been the major cause. However, rickets is also seen as a result of hereditary defects in critical vitamin D signaling molecules. Disturbances of phosphate metabolism can also lead to signs of rickets and osteomalacia, notably X-linked hypophosphatemic rickets, and oncogenic osteomalacia. Extrarenal synthesis of 1,25-dihydroxyvitamin D, such as that associated with granulomatous disease, can also lead to disturbances in calcium metabolism, with associated skeletal and nonskeletal changes.

KEYWORD

Vitamin D - rickets - osteomalacia - X-linked hypophosphatemic rickets - oncogenic osteomalacia

REFERENCES

• 1 Mawer E B. The sunshine vitamin-how a dose of sunshine forms vitamin D.  Biol Sci Rev . 1990;  2 2-7
• 2 Holick M F. Photobiology of vitamin D. In: Feldman D, Glorieux FH, Pike JW, eds. Vitamin D London: Academic Press 1997: 33-39
• 3 Stanbury S W, Mawer E B, Lumb G A. Some aspects of vitamin D metabolism in man. In: Taylor S, ed. Endocrinology London: Heinemann Medical Books 1971: 487-499
• 4 Horst R L, Reinhardt T A. Vitamin D metabolism. In: Feldman D, Glorieux FH, Pike JW, eds. Vitamin D London: Academic Press 1997: 13-31
• 5 Okuda K I, Usui E, Ohyama Y. Recent progress in enzymology and molecular biology of enzymes involved in vitamin D metabolism.  J Lipid Res . 1995;  36 1641-1652
• 6 Fraser D R, Kodiceck E. Unique biosynthesis by kidney of a biologically active vitamin D metabolite.  Nature . 1970;  288 764-766
• 7 Minghetti P P, Norman A W. 1,25(OH)₂-vitamin D3 receptors: gene regulation and genetic circuitry.  Fed Am Soc Exp Biol J . 1988;  2 3043-3053
• 8 Haussler M R, Haussler C A, Thompson P D. Molecular nature of the vitamin D receptor and its role in regulation of gene expression.  Rev End Met Dis . 2001;  2 203-215
• 9 Adams J S, Lemire J, Gacad M A, Hewison M. Vitamin D as cytokine and haematopoetic factor.  Rev End Met Dis . 2001;  2 217-227
• 10 Wasserman R H. Vitamin D and the intestinal absorption of calcium and phosphorus. In: Feldman D, Glorieux FH, Pike JW, eds. Vitamin D London: Academic Press 1997: 259-273
• 11 Barbour G L, Coburn J W, Slatopolsky E, Norman A W, Horst R L. Hypercalcemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25-dihydroxyvitamin D.  N Eng J Med . 1981;  305 440-443
• 12 Hayes M E, Denton J, Freemont A J, Mawer E B. Synthesis of the active metabolite of vitamin D, 1,25(OH)₂D3, by synovial fluid macrophages in arthritic diseases.  Ann Rheum Dis . 1989;  48 723-729
• 13 Gkonos P J, London R, Hendler E D. Hypercalcemia and elevated 1,25-dihydroxyvitamin D levels in a patient with end-stage renal disease and active tuberculosis.  N Eng J Med . 1984;  311 1683-1685
• 14 Fu G K, Lin D, Zhang M YH. Cloning of human 25-hydroxyvitamin D-1 α-hydroxylase and mutations causing vitamin D-dependent rickets type 1.  Mol Endocrinol . 1997;  11 1961-1970
• 15 Smith S J, Rucka A J, Berry J L. Novel mutations in the 1α-hydroxylase (p450c1) gene in three families with pseudovitamin D-deficiency rickets resulting in loss of functional enzyme activity in blood-derived macrophages.  J Bone Min Res . 1999;  14 730-739
• 16 Mawer E B, Davies M. Vitamin D nutrition and bone disease in adults.  Rev End Met Dis . 2001;  2 153-164
• 17 Holick M F. Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health.  Curr Opin Endo Diabetes . 2002;  9 87-98
• 18 Hebert S C, Brown E M. The extracellular calcium receptor.  Curr Opin Cell Biol . 1995;  7 484-492
• 19 Hock J M, Fitzpatrick L A, Bilezikian J P. Actions of parathyroid hormone. In: Bilezikian JP, Raisz L, Rodan GA, eds. Principles of Bone Biology, 2nd edition London: Academic Press 2002: 463-481
• 20 Mawer E B, Davies M. Bone disorders associated with gastrointestinal and hepatobiliary disease. In: Feldman D, Glorieux FH, Pike JW, eds. Vitamin D London: Academic Press 1997: 831-847
• 21 Mawer E B, Mughal Z. Rickets.  Curr Opin Ortho . 1999;  10 354-360
• 22 Clements M R, Johnston L, Fraser D R. A new mechanism for induced vitamin D deficiency in calcium deprivation.  Nature . 1987;  325 62-65
• 23 Davies M, Heys S E, Selby P L, Berry J L, Mawer E B. Increased catabolism of 25-hydroxyvitamin D in patients with partial gastrectomy and elevated 1,25-dihydroxyvitamin D levels. Implications for metabolic bone disease.  J Clin Endocrinol Metab . 1997;  82 209-212
• 24 Dunnigan M G, Henderson J B. An epidemiological model of privational rickets and osteomalacia.  Proc Nutr Soc . 1997;  56 939-956
• 25 Malloy P J, Pike J W, Feldman D. The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets.  Endo Rev . 1999;  20 156-188
• 26 Large D M, Mawer E B, Davies M. Dystrophic calcification, cataracts and enamel hypoplasia due to long standing, privational vitamin D deficiency.  Metab Bone Dis Rel Res . 1984;  5 215-218
• 27 Adams J E. Radiology of rickets and osteomalacia. In: Feldman D, Glorieux FH, Pike JW, eds. Vitamin D London: Academic Press 1997: 619-642
• 28 Parfitt A M. Vitamin D and the pathogenesis of rickets and osteomalacia. In: Feldman D, Glorieux FH, Pike JW, eds. Vitamin D London: Academic Press 1997: 645-662
• 29 Scheinman S J, Guay-Woodford L M, Thakker R V, Warnock D G. Mechanisms of disease: genetic disorders of renal electrolyte transport.  N Engl J Med . 1999;  340 1177-1187
• 30 Tieder M, Arie R, Modai D, Samuel R, Weissgarten J, Liberman U A. Elevated serum 1,25-dihydroxyvitamin D concentrations in siblings with primary Fanconi's syndrome.  N Engl J Med . 1988;  319 845-849
• 31 The HYP Consortium. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets.  Nat Genet . 1995;  11 130-136
• 32 Rowe P S. The role of the PHEX (PEX) gene in families with X-linked hypophosphatemic rickets.  Curr Opin Nephrol Hypertens . 1998;  7 367-376
• 33 Adams J E, Davies M. Intraspinal new bone formation and spinal cord compression in familial hypophosphataemic vitamin D resistant osteomalacia.  Q J Med . 1986;  61 117-129
• 34 Davies M, Kane R, Valentine J. Impaired hearing in X-linked hypophosphatemic (vitamin D resistant) osteomalacia.  Ann Int Med . 1984;  100 320-232
• 35 Tieder M, Modai D, Samuel R. Hereditary hypophosphatemic rickets with hypercalciuria.  N Eng J Med . 1985;  312 611-617
• 36 Drezner M K. Phosphorous homeostasis and related disorders. In: Bilezikian JP, Raisz L, Rodan GA, eds. Principles of Bone Biology, 2nd edition London: Academic Press 2002: 321-338
• 37 Krausz Y. Nuclear endocrinology as a monitoring tool.  Sem Nuc Med . 2001;  31 238-250
• 38 Hosking D J, Chamberlain M J, Whortland-Webb W R. Osteomalacia and carcinoma of the prostate with major redistribution of skeletal calcium.  Br J Radiol . 1975;  48 451-456
• 39 McClure J, Smith P S. Oncogenic osteomalacia.  J Clin Pathol . 1989;  40 446-453
• 40 Rathbun J C. Hypophosphatasia, a new developmental anomaly.  Am J Dis Child . 1948;  75 822-831
• 41 Whyte M P. Hypophosphatasia: nature's window on alkaline phosphatase function in man. In: Bilezikian JP, Raisz L, Rodan GA, eds. Principles of Bone Biology, 2nd edition London: Academic Press 2002: 1229-1248
• 42 Sandler L M, Winearls C G, Fraher L J. Studies on the hypercalcemia of sarcoidosis.  Q J Med . 1984;  53 165-180
• 43 Taylor R L, Lynch H J, Wysor W G. Seasonal influence of sunlight on the hypercalcemia of sarcoidosis.  Am J Med . 1963;  35 67-89
• 44 Rizzato G, Montemurro L, Fraioli P. Bone mineral content in sarcoidosis.  Semin Resp Med . 1992;  13 411-423
• 45 Davies M, Mawer E B, Hayes M E, Lumb G A. Abnormal vitamin D metabolism in Hodgkin's lymphoma.  Lancet . 1985;  1 1186-1188
• 46 Davies M, Hayes M E, Liu Yin A J, Berry J L, Mawer E B. Abnormal synthesis of 1,25-dihydroxyvitamin D in patients with malignant lymphoma.  J Clin Endocrinol Metab . 1994;  78 1202-1207
• 47 Seymour J F, Gagel R F, Hagemeister F B, Dimopoulos M A, Cabanillas F. Calcitriol production in hypercalcemic and normocalcemic patients with non-Hodgkin's lymphoma.  Ann Intern Med . 1994;  121 633-640